Septic shock is a life-threatening complication of bacterial infection. The reported number of incidences has been increased since the 1930's. Septic shock is presently the most common cause of mortality and morbidity in non-coronary intensive care units in the United States. Recent estimates suggest incidence of 70,000 to 300,000 cases per year in the United States alone. The overall mortality due to gram negative bacteremia is approximately 20%, with the occurrence of septic shock, which occurs in 15% of bacteremic patients, mortality is 50-70%.
Bacteremia is typically defined as bacteria in the bloodstream, and is usually determined by a positive blood culture. Sepsis refers to physiological alterations and clinical consequences of the presence of microorganisms or their products in the bloodstream or tissues. When sepsis is associated with hypotension and signs of poor tissue perfusion, it is called septic shock. Septic shock has traditionally been recognized as a consequence of infection with gram-negative bacteria, but it may also be caused by gram positive bacteria, fungi, viruses, and protozoa.
The pathogenesis of septic shock is complex and has not been fully understood. One of the complicating factors is that overlapping and sometimes even opposing effects can be present. Diverse microorganisms can generate toxins such that the release of potential mediators would act on vasculature and myocardium. Studies in both animals and humans have shown that endotoxin is the primary factor that precipitates the shock state. Endotoxin is a lipopolysaccharide molecule that is contained in the cell wall of all gram-negative bacteria. It is released from a focus of infection when gram-negative bacteria are phagocytized by either circulating macrophages or cells of the reticuloendothelial systems.
In the past, the conventional approach in treating endotoxin induced shock had been to administer intravenous injections of excess amounts of glucocorticoids, such as methylprednisolone at dosages of about 30 ml per kilogram. However, this method has been considered largely ineffective.
It has long been known that endotoxin will activate the complement cascade, and via the release of components of the complement system many of the effects of sepsis occur. After invading the bloodstream, microorganisms would begin a cascade of events leading to the release of microbial toxins and harmful host mediators that produce sepsis. The early mediators are thought to consist of microorganism-oriented extoxins and endotoxin, and host effectors such as neutrophils and macrophages, which produce cytokines such as tumor necrosis factor (TNF) and interleukin 1 (IL-1). The release of cytokines in low dose is normally a protective response. However, in the presence of endotoxins the massive release of TNF and subsequent activation of immune cells can lead to persistent uncontrolled systemic inflammation resulting in wide tissue injury and metabolic derangement.
Once released, cytokines would trigger a complex array of further host substances, such as prostaglandins, coagulative and fibrinolytic cascades, nitric oxide (NO), endorphins, interferons, platelet-activating factors. Overall, this network of mediators and toxins affect the systemic and pulmonary vasculatures, the myocardium, and the structures of endothelium, producing hypotension and resulting in death. NO is a potent endothelium-derived relaxing factor (EDRF); it may play a major role in the regulation of microcirculation. In the past, In vitro and in vivo studies have suggested that endotoxin-induced loss of vascular responsiveness is due to the activation of NO which is synthesized from L-arginine and can be blocked by NO synthase inhibitors L-arginine analogues, such as N-nitro-L-arginine methyl ester (L-NAME). Several studies have shown that NO has a major effect in cardiovascular performance in endotoxemia. Inhibition of NO synthesis thus has been considered as being a potentially useful method in the treatment of sepsis.
None of the prior art methods can claim a proven record of success. Therefore, other therapies must be considered to improve survival and reduce morbidity. In recent years, immunotherapy and immunoprophylaxis have been advocated. It was shown that human antiserum and monoclonal antibodies could be effective against endotoxins and TNF reduced death from gram-negative bacterial infection.
Several U.S. patents have discussed the prophylaxis and treatment of endotoxin induced shock. U.S. Pat. No. 4,388,318 ('318 patent) issued to Koyama, et al. disclosed a method of treating endotoxin shock with a pyrimido-pyrimidine derivative. The basis of the '318 patent is that central adrenergic neurons influence peripheral sympathetic nerve activity and thus cardiovascular regulation. The inhibition of alpha adrenergic receptors in vasomotor centers mediates a decrease in blood pressure, heart rate and peripheral sympathetic activity. Since E. coli endotoxin may exert its hypotensive effect by activating the central autonomic blood pressure regulatory circuits, the administering of a pyrimidopyrimidine derivative, which has a central hypertensive effect acting on the medullary cardiovascular regulatory systems, may stimulate central alpha adrenergic receptors leading to inhibition of brain stem sympathetic pathways that participate in the baroreceptor reflex system.
U.S. Pat. No. 4,822,776 ('776 patent) issued to Cerami and Kawakami disclosed an endotoxin-induced mediator substance, which they suggested may be utilized in procedures as a screening agent to test for potentially effective anti-shock agents. In the '776 patent, it was suggested that the mediator substance can be used to produce antibodies to themselves in rabbits, goats, sheep, chickens, or other mammals. These antibodies may be used as a test for the presence of the mediator substance and administered in pharmaceutical compositions in response to shock produced by viruses, bacteria, protozoa, etc.
U.S. Pat. No. 5,028,627 ('627 patent) discloses a method using arginine derivatives as arginine antagonists for prophylaxis or treatment of systemic hypotension associated with nitric oxide production or endothelial derived relaxing factor. One embodiment of the inhibitor disclosed in the '627 patent is N.sup.G -substituted arginine or an N.sup.G,N.sup.G -disubstituted arginine which is administered to animal possibly developing or having a systemic hypotension induced by a biological response modifier. The '627 patent followed the commonly accepted belief that arginine is the physiological precursor of nitric oxide synthesis; it, therefore, concluded that substituted or disubstituted arginine antagonists, such as N.sup.G -aminoarginine, N.sup.G -nitroarginine, N.sup.G -methylarginine, N.sup.G -ethylarginine, N.sup.G -propylarginine, N.sup.G -butylarginine, etc., could inhibit the production in the animal or patient of nitrogen oxide from arginine thus obviating the hypotensive effects of nitrogen oxide.
U.S. Pat. No. 5,068,314 discloses an arginine derivative, which functions as a lipopolysaccharide-binding polypeptide, for removing endotoxin. U.S. Pat. No. 5,175,183 discloses lipoxygenase inhibiting compounds, including N-aryl, N-heteroaryl, N-arylalkyl-, N-heteroarylalkyl, N-aryulcyclopropyl and N-heteroaryl-cyclopropyl-N'-hydroxyurea compounds, in treating disease states including endotoxin shock. U.S. Pat. No. 5,171,739 discloses a method for treatment of endotoxin-associated shock and prevention thereof using a BPI protein effective to bind endotoxin. U.S. Pat. No. 5,162,571 discloses phenol derivatives which have therapeutic and prophylactic activities against endotoxin shock.